The release of inflammatory cytokines such as IL-1 and tumor necrosis factor-alpha (TNFα) by leukocytes is a means by which the immune system combats pathogenic invasions, including infections. TNFα stimulates the expression and activity of adherence factors on leukocytes and endothelial cells, primes neutrophils for an enhanced inflammatory response to secondary stimuli and enhances adherent neutrophil oxidative activity. See, Sharma et al., Med. of Inflamm., 6, 175 (1987). In addition, macrophages/dendritic cells act as accessory cells processing antigen for presentation to lymphocytes. The lymphocytes, in turn, become stimulated to act as pro-inflammatory cytotoxic cells.
Generally, cytokines stimulate neutrophils to enhance oxidative (e.g., superoxide and secondary products) and nonoxidative (e.g., myeloperoxidase and other enzymes) inflammatory activity. Inappropriate and over-release of cytokines can produce counterproductive exaggerated pathogenic effects through the release of tissue-damaging oxidative and nonoxidative products (K. G. Tracey et al., J. Exp. Med., 167, 1211 (1988); and D. N. Männel et al., Rev. Infect, Dis., 2 (suppl. 5), S602-S606 (1987)). For example, TNFα can induce neutrophils to adhere to the blood vessel wall and then to migrate through the tissue to the site of injury and release their oxidative and non-oxidative inflammatory products.
Although monocytes collect slowly at inflammatory foci, given favorable conditions, the monocytes develop into long-term resident accessory cells and macrophages. Upon stimulation with an inflammation trigger, monocytes/macrophages also produce and secrete an array of cytokines (including TNFα), complement, lipids, reactive oxygen species, proteases and growth factors that remodel tissue and regulate surrounding tissue functions.
Inflammatory cytokines have been shown to be pathogenic in: arthritis (C. A. Dinarello, Semin. Immunol., 4, 133 (1992)); ischemia (A. Seekamp et al., Agents-Actions-Supp., 41, 137 (1993)); septic shock (D. N. Männel et al., Rev. Infect. Dis., 9 (suppl. 5), S602-S606 (1987)); asthma (N. M. Cembrzynska et al., Am. Rev. Respir. Dis., 147, 291 (1993)); organ transplant rejection (D. K. Imagawa et al., Transplantation, 51, 57 (1991); multiple sclerosis (H. P. Hartung, Ann. Neurol., 33, 591 (1993)); and AIDS (T. Matsuyama et al., AIDS, 5, 1405 (1991)). In addition, superoxide formation in leukocytes has been implicated in promoting replication of the human immunodeficiency virus (HIV) (S. Legrand-Poels et al., AIDS Res. Hum. Retroviruses, 6, 1389 (1990)).
A series of substituted xanthine-like compounds including pteridinediones, quinazolinones, and isoquinolones have been reported which inhibit the production or action of TNFα in human monocytes stimulated with lipopolysaccharide (LPS) in vitro. See, for example, H. B. Cottam et al., J. Med. Chem., 3, 2 (1996) and D. Carson et al. (U.S. Pat. No. 5,843,943). The most active compounds of these series were found to be in the pteridinedione class and their activity was independent of phosphodiesterase inhibition. Moreover, these compounds bind only very weakly at adenosine receptors A1, and A2, and therefore elevations in intracellular cyclic AMP levels are unlikely to play a significant role in their biological activity.
However, a continuing need exists for compounds which can block the deleterious effects of the cytokine-mediated mammalian inflammatory response.